Project Summary/Abstract The mission of the Blood and Marrow Transplant Clinical Trials Network (BMT CTN) is to ?advance hematopoietic cell transplantation (HCT) for patients with rare and difficult to treat blood diseases through high- quality multi-center clinical trials by evaluating new ways to improve traditional HCT approaches or by advancing HCT therapy through the use of either novel ex vivo manipulated cell products or genetically- modified cells.? Memorial Sloan Kettering Cancer Center (MSK) is an NCl-designated Comprehensive Cancer Center with one of the largest HCT programs in the country. The HCT program at MSK is FACT-accredited program and divided into pediatric and adult services. MSK has been a Core Member of the BMT CTN since its inception and Dr. Perales (Deputy Service Chief, grant PI), Dr. Giralt (Adult BMT Service Chief, former PI) as well as all members of the Adult BMT Service consider participation in the BMT CTN an integral part of their mission. In this grant, we detail our ongoing commitment to the success of the Network through the formation of an oversight structure that includes a BMT CTN MSK Executive Committee, a BMT CTN Protocol Management Team, and a BMT CTN Internal Advisory Board. These three administrative structures leverage not only the senior leadership of the clinical services in the Division of Hematologic Oncology, but also some of MSK's most outstanding scientists and investigators. We are also committed to continue to provide leadership to the Network with the next generation of innovative trials and correlative studies. In particular, we propose a multicenter randomized phase II trial to determine the safety and efficacy of post-HCT administration of CD19 targeted chimeric antigen receptor (CAR) T cells in patients undergoing high-dose therapy followed by autologous HCT (HDT-AHCT) for relapsed/refractory (rel/ref) DLBCL. We propose 3 specific aims: (1) Demonstrate that MSK has the clinical and translational expertise, and capabilities in novel cell therapies, genetically-modified cells, and early phase trials to fulfill the obligations of a BMT CTN Core Clinical Center that will move forward the BMT CTN mission and goals; (2) Complete a phase II study in which rel/ref DLBCL patients will receive 3 monthly infusions of CD19 CAR T cells after HDT-AHCT. In Arm 1, the 1st infusion will be day +3 after HCT, with later infusions on days +30 and +60. In Arm 2, the 1st infusion will be day +10, with later infusions on the same Arm 1 schedule. The primary endpoint will be PFS at a 1-year. A pick-the-winner design will be used for the study; (3) Assess quantitative persistence and qualitative function of CAR T cells and correlate to: serum cytokine profiles, B cell aplasia, and clinical outcomes. This research is significant as it proposes a novel treatment paradigm in patients with relapsed DLBCL resistant to standard-dose 2nd-line chemotherapy, who typically would have long-term EFS with HDT-AHCT of only 10-15%. The proposed study is highly relevant to the BMT CTN, since it presents an innovative cell therapy, u s i n g genetically modified cells to improve outcomes in patients with advanced lymphoid malignancies, including rel/ref DLBCL.